Phenylacetic acids and their salts

ABSTRACT

WHERE R represents an hydrogen or a methyl radical. Compounds of formula (1) and their metallic and amine salts are very useful substances in human therapeutics, namely as analgesic, antipyretic and antiinflamatory medicines. Compounds of formula (1) are prepared by reacting a 2phenothiazinylacetic acid of formula:   Phenylacetic acid derivatives having the formula: WITH A DESULFURIZING REDUCING AGENT.   D R A W I N G

United States Patent Boissier et a1.

[451 Oct. 10,1972

[54] PHENYLACETIC ACIDS AND THEIR SALTS [72] Inventors: Jacques R. Boissier, Paris; Roger 21 Appl. No; 848,141

[30] Foreign Application Priority Data July 30, 1968 France ..68l6l159 Oct. 24, 1968 [52] US. Cl ..260/518 R, 260/243 A, 424/319 [51] Int. Cl ..C07c 101/44 [58] Field of Search ..260/5 18 R, 243 A [56] References Cited UNITED STATES PATENTS 9/1963 Spacht ..260/243 AB OTHER PUBLICATIONS Theilheimer, W. Synthetic Methods of Organic Chemistry," Vol. 18 (1964), pub. S. Krager, N.Y. QD242 T4C2 Page 55.

France ..68l7l2l7 Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. Arnold Thaxton Att0rneyDavis, Hoxie, Faithfull & l-Iapgood [57] ABSTRACT Phenylacetic acid derivatives having the formula:

H HPCOzH I (l) where R represents an hydrogen or a methyl radical.

Compounds of formula (1) and their metallic and amine salts are very useful substances in human therapeutics, namely as analgesic, antipyretic and antiinflamatory medicines.

Compounds of formula (1) are prepared by reacting a 2-phenothiazinylacetic acid of formula:

with a desulfurizing reducing agent.

3 Claims, No Drawings where R represents an hydrogen atom or a methyl radical.

According to the invention, the process for the preparation of the compounds of formula (1) comprises reacting a 2-phenothiazinylacetic acid of formu- \N/ CHr-C 0211 where R has the meaning defined above, with a desulfurizing reducing agent and isolating the resulting compound of formula l A desulfurizing reducing agent means a reducing agent able to break the carbon-sulfur bonds and to form two new carbon hydrogen bonds on the two benzene rings (desulfuration reaction).

In the preferred conditions for carrying out the process, the desulfurizing reducing agent used is: either hydrogen, generated in situ by reacting an aqueous sodium hydroxide solution with Raney nickel alloy (nickel aluminum alloy); this alloy can advantageously be added gradually to the mixture of compound of formula (2) with an aqueous solution of sodium hydroxide; at the end of the addition, the reactive mixture can advantageously be heated on water bath to finish off the reaction; mineral products are then separated by filtration and the desired compound of formula (1) is isolated from the aqueous filtrate by acidification and extraction, or hydrogen iodide in the form of aconcentrated aqueous solution. In this case the mixture of the compound of formula (2) and of the aqueous solution of hydrogen iodide is boiled under reflux for hours to 40 hours. At the completion of the reaction the desired compound formula l) is isolated from the reaction mixture by extraction.

According to an alternative method of the process of the invention, the compounds of formula l) where R represents a methyl radical, can be prepared by reacting a compound of formula (1) where R is a hydrogen atom and an alkali-metal compound, such as sodium amide, capable of replacing the hydrogen atom with an alkali-metal atom; and then condensing the resulting metallic compound with a methylating agent.

This alternative method is preferentially carried out by using sodium amide, as the alkali-metal compound, in liquid ammonia, and methyl iodide as the methylating agent. Preferably, at least two moles of sodium amide and two moles of methyl iodide are used per mole of compound to be methylated. The action of the methyl iodide is preferentially performed in anhydrous ether. When the reaction is over, the compounds of formula (l) where R represents a methyl radical is isolated from the reaction mixture by acidification and extraction.

Salts of acids of the above formula (I) can be prepared, according to the invention, by reacting corresponding mineral bases or amines with said acids, performing the reaction in a solvent such as a lower alcohol (for instance methanol or ethanol). Said mineral bases may be, for instance, alkaline bases, alkalineearth bases or ammonia. When the reaction is over, the solvent may be removed by concentration under vacuum and the resulting salt may be purified by recrystallization.

The compounds of formula (1) and their salts are useful substances for human therapeutics namely because of their remarkable analgesic, antipyretic and antiinflammatory properties.

Pharmacological studies of the compounds of this invention have shown their great activity and interest. The activity of the following two compounds was studied in detail: (3-anilino phenyl) acetic acid (hereinafter referred as S. D. 2 l l l0l and (N-methyl 3-anilino phenyl) sodium acetate (hereinafter referred as S. D. 2 111-02). Pharmacological tests and their results were as follows.

Analgesic power was studied in mice, by means of the phenylbenzoquinone test according to SlEGMUND et al. (Proc. Soc. Exper. Biol. N. Y. 1957, 95, 729). Protection by the administration of a tested compound was expressed in percentage according to the following formula:

% protection Results were as follows:

TABLE Administered doses of protection (mg/kg per os) S.D.2lll-0l S.D.2lll-02 of inhibition= [1 A represents the hourly algebric variation of rectal temperature with regard to the initial rectal temperature, temperatures being noted at hourly intervals for 6 hours. Under the conditions the SD. 2 l l 1-0] produced an inhibition of 56 percent and the SD. 2 1 11-02 of 93 percent.

Antiinflammatory activity was evaluated in guineapigby means of the tetrahydrofurfuryl nicotinat test according to HAlNlNGs technic (Brit. J. Pharmacol. 1963,21, 104). Tested products being administered per os, SD. 2 l 1 1-01 was able to insure a partial protection from the dose of 50 mg/kg and a complete protection from the .dose of 200 mg/kg; SD. 2 l 1 l02 was able to insure a partial protection from the dose of 10 mg/kg and a complete protection from the dose of 50 mg/kg.

Itwas observed that tested compounds are endowed with a low toxicity since, for instance, the oral administration in mice of 1 g/kg of SD. 2 1 11-01 did not induce any mortality and since under the same conditions and for the same dose SD. 2 Ill-02 induced only 30 percent of the mortality.

Owing to their pharmacological activities compounds of formula (1) and their salts are useful medicines namely in the treatment of various algies, of febrile diseases, of acute or chronical rheumatisrns. The usual dose varies according to the used product, the treated patient, the concerned complaint; it may be for instance from 0.250 g to 2.5 g per day, per 08 in human beings.

As medicines, these substances can be employed either, in the form of acids or in the form of pharmaceutically acceptable salts. Such salts can be for instance salts obtained with alkali metals, alkaline-earth metal or ammonium.

The present invention isalsoconcemed with the pharmaceutical compositions which comprise as active principle one or several of the compounds of formula (1) and/or their metallic salts and/or their salts of amines. These. compositions are prepared so that they can be administered by digestive, parenteral or local routes. They may be solid or liquid and be provided in the pharmaceutical forms usually employed in human medicine, such as for example tablets, coated or not, capsules, granulated substances, suppositories, parenteral preparations, ointments, creams and gels; they are prepared according to usual methods. The active principle or principles thereof may be incorporated with usual excipients, which are normally used in those pharmaceutical compositions, such as talcum, arabic gum, lactose, starch magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, various animal or vegetable fatty substances, paraffins, glycols, various wetting, dispersing and emulsifying agents, preservatives.

The following non limiting examples illustrate the invention EXAMPLE 1 3- Anilino phenyl) acetic acid v 10 g of Z-phenothiazinylacetic acid were suspended in 1 l of a 10 percent sodium hydroxide solution containing 5 ml of n-amyl alcohol. Then, 100 g of Raney nickel alloy were added in small portions, with stirring. When the addition was over, the mixture was heated on a steam-bath for 2 hours. Insoluble matter was separated from the solution by filtration while hot, and washed with 100 ml of a percent sodium hydroxide solution. The alkaline solutions were then collected,

cooled, and acidified by adding concentrated hydrochloric acid. The product which had separated was extracted with ether. Evaporation of the dried (sodium sulfate) ethereal solution gave a cristalline product which was recrystallized from benzene to give 5 g (56 percent) of (3-anilino phenyl) acetic acid as white crystals. Melting point l38-l40 C on open capillary.

EXAMPLE 2 (3-Anilino phenyl) acetic acid A mixture of 10 g of 2-phenothiazinylacetic acid and ml of 57 percent hydriodic acid was boiled for 20 hours under reflux with stirring. After cooling, the mixture was diluted with water and extracted with ether. Ethereal brown phase was washed with an aqueous sodium thiosulfate solution until decoloration, then with water. Evaporation of the dried (sodium sulfate) ethereal solution gave a cristalline product which was recrystallized from benzene to give 5.5 g (62 percent) of (3-anilino phenyl) acetic acid as white crystals. This product was identical with the one obtained according to the process described in example 1. Melting point l38l40 C on open capillary.

Analysis: C H N 0 Calculated 7410 5.8 6.2

Found 74.0 5.9 6.2

EXAMPLE 3 (N-methyl 3-anilino phenyl )acetic acid Following the procedure described in example 1, but starting from 10 g of 2-(l0-methyl phenothiazinyl) acetic acid, the aqueous acid solution was extracted with benzene benzenic extracts were evaporated under vacuum to give 7.5 g (84 percent) of (N-methyl 3-anilino phenyl)acetic acid as a light yellow oil which cristallized slowly. Melting point on a hot stage microscope: 4750 C.

EXAMPLE 4 (N-methyl 3-anilino phenyl) sodium acetate 30.5 ml of a N aqueous sodium hydroxide solution were added to the solution of 7.5 g of (N-methyl 3- anilino phenyl) acetic acid, obtained according to the process described in example 3, in 50 ml of ethanol. Solvents were removed under vacuum and the resulting solid residue was washed with benzene. After drying, the residue was recrystallized from 60 ml of isopropanol to give 5 g (61 percent) of (N-methyl 3- anilino phenyl) sodium acetate as water-soluble white crystals. Melting point: l36l40 C on a hot stage microscope.

Analysis: C H N Na 0 C H Calculated 68.4 5.4 Found 68.8 5.5

EXAMPLE 5 (N-methyl 3-anilino phenyl) acetic acid 6 g (0.0265 mole) of (3-anilino phenyl) acetic acid prepared according to the process described in example l were added in small portions to a suspension of 2.3 g (0.059 mole) of sodium amide in 150 ml of liquid minutes, then a solution of 8.3g (0.059 mole) of methyl iodide in 50 ml of anhydrous ether was added dropwise and the mixture was stirred for 30 minutes. Ammonia was removed and 100 ml of water and 50 ml of ether were successively added. Aqueous phase was separated by decantation, acidified by adding 60 ml of a N aqueous hydrochloric acid solution and extracted with benzene. Benzene was removed under vacuum to give 5.5 g (83 percent) of (N-methyl 3-anilino phenyl) acetic acid as a yellow oil which cristallized slowly. Melting point on a hot stage microscope 4750 C. This product is identical to the one obtained by the process described in example 3.

EXAMPLE 6 Tablets were prepared which corresponded to the formula:

(3-anilino phenyl) acetic acid Excipient s.q. to make I00 mg (Excipient stearate lactose, starch, talcum, magnesium EXAMPLE 7 Tablets were prepared which correspond to the formula:

EXAMPLE 8 Suppositories were prepared which corresponded to the formula (N-methyl 3-anilino phenyl) sodium acetate 0.200 g Excipient s.q. to make 3 g EXAMPLE 9 Parenteral preparations were realized which corresponded to the formula (N-methyl 3-anilino phenyl) sodium acetate 400 mg Excipient s.q. to make 4 ml EXAMPLE 10 An ointment was prepared which corresponded to the formula (N-methyl 3-anilino phenyl) sodium Excipient s.q. to make wherein R is a member selected from the group consistf h dro n atom and a meth l radical. 5. A coknpiiid selected from thi; group consisting of (3-anilino phenyl) acetic acid, and its alkali-metal, alkaline-earth metal and ammonium salts.

3. A compound selected from the group consisting of (N-methyl 3-anilino phenyl) acetic acid, and its alkali-' 5 metal, alkaline-earth metal and ammonium salts. 

2. A compound selected from the group consisting of (3-anilino phenyl) acetic acid, and its alkali-metal, alkaline-earth metal and ammonium salts.
 3. A compound selected from the group consisting of (N-methyl 3-anilino phenyl) acetic acid, and its alkali-metal, alkaline-earth metal and ammonium salts. 